Tim-3 mediates T cell trogocytosis to limit antitumor immunity

Introduction During chronic viral infection and cancer, tumor antigen-specific (TA-specific) [CD8.sup.+] T cells become dysfunctional and upregulate multiple inhibitory receptors, including programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) and [...]
T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1-positive ([PD-1.sup.+]) [Tim-3.sup.+][CD8.sup.+] tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on [Tim-3.sup.+] APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen-specific [CD8.sup.+] T cells and [PD-1.sup.+][Tim-3.sup.+] [CD8.sup.+] TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of [CD8.sup.+] TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in [CD8.sup.+] T cells impeded the trogocytosis of [CD8.sup.+] TILs in vivo. Trogocytosed [CD8.sup.+] T cells presented tumor peptide-major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity.